Fluid mixing systems with adjustable mixing element

ABSTRACT

A fluid mixing system includes a support housing having an interior surface bounding a chamber. A flexible bag is disposed within the chamber of the support housing, the flexible bag having an interior surface bounding a compartment. An impeller is disposed within the chamber of the flexible bag. A drive shaft is coupled with the impeller such that rotation of the drive shaft facilitates rotation of the impeller. A drive motor assembly is coupled with the draft shaft and is adapted to rotate the drive shaft. An adjustable arm assembly is coupled with the drive motor assembly and is adapted to move the drive motor assembly which in turn moves the position of the drive shaft and impeller. An electrical controller can control movement of the adjustable arm.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application No.61/551,159, filed Oct. 25, 2011, which is incorporated herein byspecific reference in its entirety.

BACKGROUND OF THE INVENTION 1. The Field of the Invention

The present invention relates to methods and systems for mixing fluids,namely, biological fluids.

2. The Relevant Technology

The biopharmaceutical industry uses a broad range of mixing systems fora variety of processes such as in the preparation of media and buffersand in the growing of cells and microorganisms in bioreactors. Someconventional mixing systems, including bioreactors, comprise a flexiblebag disposed within a rigid support housing. An impeller is disposedwithin the flexible bag and is used to mix or suspend the solutionwithin the bag. In some embodiments, the impeller is mounted to thebottom of the bag and is magnetically driven. In other embodiments, theimpeller is fixed on the end of a drive shaft that projects into theflexible bag. In both embodiments, however, the impeller is designed toremain at a substantially fixed position which is optimal for mixing anarrowly defined volume of solution in the flexible bag. To enablehomogeneous mixing of larger volumes of solution, larger bags are usedthat have an impeller positioned at a location that is optimal for thatsize of bag.

In some processing procedures it can be desirable to initially mixsolutions at a low volume and then progressively increase the volume ofthe solution. For example, this is a common procedure used withbioreactors for growing cells. The process typically entails dispensinga seed inoculum in a growth media contained within a relatively smallbag and then transferring the solution to progressively larger bagswhere additional media is added as the cells grow and multiple. Thisprocess is repeated until a final desired volume is achieved. Bytransferring the solution to different sized bags which each have acorresponding mixer, the operator can ensure homogeneous mixing of eachof the different volumes.

Although the above process of moving solutions to different sized bagsto maintain proper mixing and suspension is functional, the procedurehas some shortcomings. For example, the necessity of stepping todifferent sized bags is labor intensive, time consuming, and has highmaterial costs in that the multiple bags are discarded after use.Furthermore, transferring between different bags produces some mixingdown-time which can influence cell growth. In addition, the necessity ofshifting between bags increases the risk of contamination to thesolution and potential damage to the cells.

Accordingly, what is needed in the art are improved mixing systems thatsolve all or some of the above problems.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention will now be discussed withreference to the appended drawings. It is appreciated that thesedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting of its scope.

FIG. 1 is a perspective view of a fluid mixing system;

FIG. 2 is a perspective view of the container assembly of the fluidmixing system shown in FIG. 1 ;

FIG. 2A is a perspective view of an alternative container assembly;

FIG. 3 is an elevated side view of an impeller assembly of the containerassembly shown in FIG. 2 and a drive shaft;

FIG. 4 is a partially disassembly perspective view of a drive motorassembly of the fluid mixing system shown in FIG. 1 in association withthe impeller assembly and drive shaft of FIG. 3 ;

FIG. 5 is a right side perspective view of the adjustable arm assemblyof the mixing system shown in FIG. 1 ;

FIG. 6 is a left side perspective view of the adjustable arm assemblyshown in FIG. 5 ;

FIG. 7 is a front perspective view of the drive motor assembly androtational assembly;

FIG. 8 is an elevated front view of the rotational assembly shown inFIG. 7 coupled with the drive motor assembly;

FIG. 9 is a perspective view of an alternative embodiment of a containerbeing used with a drive motor assembly and impeller assembly;

FIG. 10 is a perspective view of an alternative embodiment of theimpeller assembly shown in FIG. 9 ;

FIG. 11 is a perspective view of another alternative embodiment of amixing system incorporating features of the present invention;

FIG. 12 is a right side perspective view of the adjustable arm assemblyof the mixing system shown in FIG. 11 ;

FIG. 13 is a left side perspective view of the adjustable arm assemblyshown in FIG. 12 ;

FIG. 14 is a block diagram showing the controller of the mixing systemshown in FIG. 12 electrically coupled to other components of the mixingsystem;

FIG. 15 is a cross sectional side view of one embodiment of the supporthousing shown in FIG. 11 ;

FIG. 16 is a cross sectional side view of an alternative embodiment aflexible container having a dish mounted to the floor thereof and asupport housing configured to receive the container;

FIG. 17 is a schematic top plan view of the support housing shown inFIG. 11 showing rotation and movement of the drive shaft; and

FIG. 18 is a cross sectional side view of an alternative embodiment of adrive shaft coupled to a flexible container by a dynamic seal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used in the specification and appended claims, directional terms,such as “top,” “bottom,” “left,” “right,” “up,” “down,” “upper,”“lower,” “proximal,” “distal” and the like are used herein solely toindicate relative directions and are not otherwise intended to limit thescope of the invention or claims.

The present invention relates to systems and methods for mixing and, ifdesired, sparging solutions and/or suspensions. The systems can becommonly used as bioreactors or fermentors for culturing cells ormicroorganisms. By way of example and not by limitation, the inventivesystems can be used in culturing bacteria, fungi, algae, plant cells,animal cells, protozoan, nematodes, and the like. The systems canaccommodate cells and microorganisms that are aerobic or anaerobic andare adherent or non-adherent. The systems can also be used inassociation with the formation and/or treatment of solutions and/orsuspensions that are for biological purposes, such as media, buffers, orreagents. The systems can also be used for mixing powders or othercomponents into a liquid where sparging is not required and/or where issolution is not for biological purposes.

Some embodiments of the inventive systems are designed so that amajority of the system components that contact the material beingprocessed can be disposed of after each use. As a result, the inventivesystems substantially eliminate the burden of cleaning and sterilizationrequired by conventional stainless steel mixing systems. This featurealso ensures that sterility can be consistently maintained duringrepeated processing of multiple batches. The inventive systems are alsoadjustable so that they can be used for mixing a variety of differentbatch sizes. In view of the foregoing, and the fact that the inventivesystems are easily scalable, relatively low cost, and easily operated,the inventive systems can be used in a variety of industrial andresearch facilities that previously outsourced such processing.

Some embodiments of the present invention also enable manual orautomatic adjustment of the position, tilt, and/or movement pattern ofthe mixing element within the solution. This ability to adjust theposition, tilt, and/or movement pattern of the mixing element enablesoptimal mixing or suspension of the solution as the volume, propertiesor critical processing parameters of the solution varies.

Depicted in FIG. 1 is one embodiment of an inventive mixing system 10Aincorporating features of the present invention. In general, mixingsystem 10A comprises a support housing 78, a cart 80A on which on whichsupport housing 78 rests, a drive motor assembly 300, an adjustable armassembly 302A which supports drive motor assembly 300 on support housing78, a container assembly 16 that is supported within support housing 78,and drive shaft 362 (FIG. 3 ) that extends between drive motor assembly300 and container assembly 16. The various components of mixing system10A will now be discussed in greater detail.

As depicted in FIG. 2 , container assembly 16 comprises a container 18having a side 20 that extends from an upper end 22 to an opposing lowerend 24. Upper end 22 terminates at an upper end wall 23 while lower end24 terminates at a lower end wall 24. Container 18 also has an interiorsurface 26 that bounds a compartment 28. Compartment 28 is configured tohold a fluid. In the embodiment depicted, container 18 comprises aflexible bag that is comprised of a flexible, water impermeable materialsuch as a low-density polyethylene or other polymeric sheets having athickness in a range between about 0.1 mm to about 5 mm with about 0.2mm to about 2 mm being more common. Other thicknesses can also be used.The material can be comprised of a single ply material or can comprisetwo or more layers which are either sealed together or separated to forma double wall container. Where the layers are sealed together, thematerial can comprise a laminated or extruded material. The laminatedmaterial comprises two or more separately formed layers that aresubsequently secured together by an adhesive.

The material is approved for direct contact with living cells and iscapable of maintaining a solution sterile. In such an embodiment, thematerial can also be sterilizable such as by ionizing radiation.Examples of materials that can be used in different situations aredisclosed in U.S. Pat. No. 6,083,587 which issued on Jul. 4, 2000,United States Patent Publication No. US 2003/0077466 A1, published Apr.24, 2003, and United States Patent Publication No. US 2011/0310696 A1,published Dec. 22, 2011 which are incorporated herein by specificreference.

In one embodiment, container 18 comprise a two-dimensional pillow stylebag such as where two sheets of material are placed in overlappingrelation and the two sheets are bonded together at their peripheries toform the internal compartment. In other embodiments, as depicted in FIG.2 container 18 can comprise a three-dimensional bag that not only has anannular side wall but also a two dimensional top end wall and a twodimensional bottom end wall. Further disclosure with regard tothree-dimensional bags and method of manufacturing are disclosed inUnited States Patent Publication No. US 2002-0131654 A1, published Sep.19, 2002 and United States Patent Publication No. US 2011/0310696 A1,published Dec. 22, 2011 which are incorporated herein by specificreference.

It is appreciated that container 18 can be manufactured to havevirtually any desired size, shape, and configuration. For example,container 18 can be formed having a compartment sized to 10 liters, 30liters, 100 liters, 250 liters, 500 liters, 750 liters, 1,000 liters,1,500 liters, 3,000 liters, 5,000 liters, 10,000 liters or other desiredvolumes. The size of the compartment can also be in the range betweenany two of the above volumes. Although container 18 can be any shape, inone embodiment container 18 is specifically configured to becomplementary or substantially complementary to the chamber of supporthousing 78 in which container 18 is received so that container 18 isproperly supported therein when filled with fluid.

Although in the above discussed embodiment container 18 has a flexible,bag-like configuration, in alternative embodiments it is appreciatedthat container 18 can comprise any form of collapsible container orsemi-rigid container. For example, the container can be accordioned orcontain baffles that permit the container to expand and contract. Inother embodiments, portions of the container can be rigid while otherportions are flexible. Container 18 can also be transparent or opaqueand can have ultraviolet light inhibitors incorporated therein.

Continuing with FIG. 2 , formed on container 18 are a plurality of ports30 at upper end 22 and a plurality of ports 31 at lower end 24. Each ofports 30, 31 communicate with compartment 28. Although only a few ports30, 31 are shown, it is appreciated that container 18 can be formed withany desired number of ports 30, 31 and that ports 30, 31 can be formedat any desired location on container 18 including along side 20 and onupper end wall 23 an lower end wall 25. Ports 30, 31 can be the sameconfiguration or different configurations and can be used for a varietyof different purposes. For example, ports 30, 31 can be coupled withfluid lines for delivering media, cell cultures, gases and/or othercomponents into container 18 and also withdrawing gases and fluids fromcontainer 18.

Ports 30, 31 can also be used for coupling probes and/or sensors tocontainer 18. For example, when container 18 is used as a bioreactor forgrowing cells or microorganisms, ports 30, 31 can be used for couplingprobes such as temperatures probes, pH probes, dissolved oxygen probes,dissolved CO₂ probes and the like. Various optical sensors and othertypes of sensors can also be attached to ports 30, 31. Examples of ports30, 31 and how various probes, sensors, and lines can be coupled theretois disclosed in United States Patent Publication No. 2006-0270036,published Nov. 30, 2006 and United States Patent Publication No.2006-0240546, published Oct. 26, 2006, which are incorporated herein byspecific reference. Ports 30, 31 can also be used for coupling container18 to secondary containers, to condenser systems, and to other desiredfittings.

In one embodiment of the present invention, container assembly 16includes means for delivering a gas into the lower end of container 18.By way of example and not by limitation, container assembly 16 cancomprise a sparger 34 positioned either on or mounted to lower end 24 ofcontainer 18 for delivering a gas to the fluid within container 18. Asis understood by those skilled in the art, various gases are typicallyrequired in the growth of cells or microorganisms within container 18.The gas typically comprises air that is selectively combined withoxygen, carbon dioxide and/or nitrogen. However, other gases can also beused. The addition of these gases can be used to regulate the dissolvedoxygen content and pH of a culture. A gas line 36 is coupled withsparger 34 for delivering the desired gas to sparger 34. Gas line 36need not pass through lower end 24 of container 18 but can extend downfrom upper end 22 or from other locations.

Sparger 34 can have a variety of different configurations. For example,sparger 34 can comprise a permeable membrane or a fritted structurecomprised of metal, plastic or other materials that dispense the gas insmall bubbles into container 18. Smaller bubbles can permit betterabsorption of the gas into the fluid. In other embodiments, sparger 34can simply comprise a tube, port, or other type opening formed on orcoupled with container 18 through which gas is passed into container 18.In contrast to being disposed on container 18, the sparger can also beformed on or coupled with impeller 64, which is discussed below.Examples of spargers and how they can be used in the present inventionare disclosed in United States Patent Publication Nos. 2006/0270036 and2006/0240546 which were previously incorporated by reference. Otherconventional spargers can also be used.

Container assembly 16 further comprises an impeller assembly 40. Asdepicted in FIG. 3 , impeller assembly 40 comprises an elongated tubularconnector 44 having a rotational assembly 48 mounted at one end and animpeller 64 mounted on the opposing end. More specifically, tubularconnector 44 has a first end 46 and an opposing second end 48 with apassage 51 that extends therebetween. In one embodiment, tubularconnector 44 comprises a flexible tube such as a polymeric tube. Inother embodiments, tubular connector 44 can comprise a rigid tube orother tubular structure.

Rotational assembly 48 is mounted to first end 46 of tubular connector44. Rotational assembly 48 comprises an outer casing 50 having anoutwardly projecting flange 52 and a tubular hub 54 rotatably disposedwithin outer casing 50. A bearing assembly can be disposed between outercasing 50 and tubular hub 54 to permit free and easy rotation of hub 54relative to casing 50. Likewise, one or more seals can be formed betweenouter casing 50 and tubular hub 54 so that during use an aseptic sealcan be maintained between outer casing 50 and tubular hub 54 as tubularhub 54 rotates relative to outer casing 50.

Hub 54 has an interior surface 56 that bounds an opening 58 extendingtherethrough. As will be discussed below in greater detail, an engagingportion of interior surface 56 has a polygonal or other non-circulartransverse cross section so that a driver portion of drive shaft 362passing through opening 58 can engage the engaging portion andfacilitate rotation of hub 54 by rotation of drive shaft 362. Hub 54 canalso comprise a tubular stem 60 projecting away from outer casing 50.Hub 54 can couple with first end 46 of tubular connector 44 by stem 60being received within first end 46. A pull tie, clamp, crimp or otherfastener can then be used to further secure stem 60 to tubular connect44 so that a liquid tight seal is formed therebetween. Otherconventional connecting techniques can also be used.

Impeller 64 comprises a central hub 66 having a plurality of fins 68radially outwardly projecting therefrom. It is appreciated that avariety of different numbers and configurations of fins 68 can bemounted on hub 66. Hub 66 has a first end 70 with a blind socket 72formed thereat. Socket 72 typically has a noncircular transverse crosssection, such as polygonal, so that it can engage a driver portion ofdrive shaft 362. Accordingly, as will be discussed below in greaterdetail, when a driver portion is received within socket 72, the driverportion engages with impeller 64 such that rotation of drive shaft 362facilities rotation of impeller 64.

In one embodiment, hub 66 and fins 68 of impeller 64 are molded from apolymeric material. In alternative embodiments, hub 66 and fins 68 canbe made of metal, composite, or a variety of other materials. Ifdesired, an annular insert can be positioned within socket 72 to helpreinforce hub 66. For example, the insert can be comprised of metal orother material having a strength property greater than the material fromwhich hub 66 is comprised.

Impeller 64 can be attached to connector 44 by inserting first end 70 ofhub 66 within connector 44 at second end 48. A pull tie, clamp, crimp,or other type of fastener can then be cinched around second end 48 ofconnector 44 so as to form a liquid tight sealed engagement betweenimpeller 64 and connector 44.

Returning to FIG. 2 , rotational assembly 48 is secured to container 18so that tubular connector 44 and impeller 64 extend into or are disposedwithin compartment 28 of container 18. Specifically, in the depictedembodiment container 18 has an opening 74 at upper end 22. Flange 52 ofouter casing 50 is sealed around the perimeter edge bounding opening 74so that hub 54 is aligned with opening 74. Tubular connector 44 havingimpeller 64 mounted on the end thereof projects from hub 54 (FIG. 3 )into compartment 28 of container 18. In this configuration, outer casing50 is fixed to container 18 but hub 54, and thus also tubular connector44 and impeller 64, can freely rotate relative to outer casing 50 andcontainer 18. As a result of rotational assembly 48 sealing opening 74,compartment 28 is sealed closed so that it can be used in processingsterile fluids.

As depicted in FIG. 3 , impeller assembly 40 is used in conjunction withdrive shaft 362. In general drive shaft 362 comprises a head section 364and a shaft section 366 that can be coupled together by threadedconnection or other techniques. Alternatively, drive shaft 362 can beformed as a single piece member or from a plurality of attachablesections. Drive shaft 362 has a first end 368 and an opposing second end370. Formed at first end 368 is a frustoconical engaging portion 372that terminates at a circular plate 374. Notches 376 are formed on theperimeter edge of circular plate 374 and are used for engaging driveshaft 362 with a drive motor assembly as will be discussed below.

Formed at second end 370 of drive shaft 362 is a driver portion 378.Driver portion 378 has a non-circular transverse cross section so thatit can facilitate locking engagement within hub 66 of impeller 64. Inthe embodiment depicted, driver portion 378 has a polygonal transversecross section. However, other non-circular shapes can also be used. Adriver portion 380 is also formed along drive shaft 362 toward first end368. Driver portion 380 also has a non-circular transverse cross sectionand is positioned so that it can facilitate locking engagement withinthe interior surface of hub 54 of rotational assembly 48.

During use, as will be discussed below in further detail, drive shaft362 is advanced down through hub 54 of rotational assembly 48, throughtubular connecter 44 and into hub 66 of impeller 64. As a result of theinterlocking engagement of driver portions 378 and 380 with hubs 66 and54, respectively, rotation of drive shaft 362 by a drive motor assemblyfacilitates rotation of hub 54, tubular connecter 44 and impeller 64relative to outer casing 50 of rotational assembly 48. As a result ofthe rotation of impeller 64, fluid within container 18 is mixed.

It is appreciated that impeller assembly 40, drive shaft 362 and thediscrete components thereof can have a variety of differentconfiguration and can be made of a variety of different materials.Alternative embodiments of and further disclosure with respect toimpeller assembly 40, drive shaft 362, and the components thereof aredisclosed in US Patent Publication No. US 2011/0188928 A1, publishedAug. 4, 2011 and US Patent Publication No. US 2011/0310696 A1, publishedDec. 22, 2011 which are hereby incorporated by specific reference.

Depicted in FIG. 2A is an alternative container assembly 16A which canbe used in place of container assembly 16. Container assembly 16Acomprises container 18 having impeller assembly 40 attached thereto thesame as in container assembly 16. However, in contrast to containerassembly 16 which was designed to function as part of a fermentor orbioreactor, container assembly 16A is primarily designed for mixing andtransporting fluids. As such, sparger 34 of container assembly 16 hasbeen removed and replaced with a port 422 centrally secured on a floor424 of container 18. A drain line 426, which is typically in the form ofa flexible tube, is coupled to and extends from port 420. A hose clamp427, as is known in the art, can be attached to drain line 426 forcontrolling the flow of fluid therethrough.

Returning to FIG. 1 , support housing 78 has a substantially cylindricalsidewall 82 that extends between an upper end 84 and an opposing lowerend 86. Lower end 86 has a floor 88 mounted thereto. As a result,support housing 14 has an interior surface 90 that bounds a chamber 92.An annular lip 94 is formed at upper end 84 and bounds an opening 96 tochamber 92. As discussed above, chamber 92 is configured to receivecontainer assembly 16 so that container 18 is supported therein.

Although support housing 78 is shown as having a substantiallycylindrical configuration, in alternative embodiments support housing 78can have any desired shape capable of at least partially bounding acompartment. For example, sidewall 82 need not be cylindrical but canhave a variety of other transverse, cross sectional configurations suchas polygonal, elliptical, or irregular. Furthermore, it is appreciatedthat support housing 78 can be scaled to any desired size. For example,it is envisioned that support housing 78 can be sized so that chamber 92can hold a volume of less than 50 liters, more than 1,000 liters or anyof the other volumes or range of volumes as discussed above with regardto container 18. Support housing 78 is typically made of metal, such asstainless steel, but can also be made of other materials capable ofwithstanding the applied loads of the present invention.

It is appreciated that floor 88 of support housing 78 can be formed witha central opening extending therethrough for gas line 36 (FIG. 2 ) topass. In addition, any desired number of openings can be formed throughsidewall 82 at lower end 86 to permit access to ports 31 (FIG. 2 ). Oneor more larger openings that are closed by a door can also be formedthrough sidewall 82 at lower end 86. The larger openings enable anoperator to reach into chamber 92 for aligning container 18 and passinggas line 36 (FIG. 2 ) through the floor opening.

In one embodiment of the present invention, means are provided forcontrolling the temperature of the fluid within container 18 whencontainer 18 is disposed within support housing 78. As one example ofthe means, support housing 78 is jacketed having a fluid inlet 184 and afluid outlet 186. The jacket enables heated or cooled fluid to passthrough support housing 78 for controlling the temperature of the fluidwithin container 18. In an alternative embodiment, electrical heatingelements can be mounted on or within support housing 78. Alternatively,the temperature can be controlled by applying gas burners to supporthousing 78 or pumping the fluid out of container 18, heating the fluidand then pumping the fluid back into container 18.

Further discussion with regard to openings that can be formed on supporthousing 78, the jacketing of support housing 78 and other alternativefeatures for support housing 78 are disclosed in US Patent PublicationNo. US 2011/0310696 A1, published Dec. 22, 2011 which is incorporatedherein by specific reference.

As also depicted in FIG. 1 , cart 80A comprises a platform 190 having atop surface 192 and an opposing bottom surface 194. In the depictedembodiment, platform 190 has a substantially square configuration. Inalternative embodiments, however, platform 190 can be triangular,rectangular, circular, or of other polygonal or irregularconfigurations. Downwardly projecting from bottom surface 194 are aplurality of spaced apart wheels 196. A plurality of spaced apart legs198 extend between floor 88 of support housing 78 and top surface 192 ofplatform 190. Legs 198 provide an open gap between support housing 78and platform 190 so as to enable access to floor 88. In otherembodiments, cart 80A can be eliminated and support housing 78 can besupported by legs 198 on a ground or floor surface or on a pallet orother support structure.

As also shown in FIG. 1 , drive motor assembly 300 is coupled withsupport housing 78 by adjustable arm assembly 302A. Drive motor assembly300 is used in conjunction with drive shaft 362 (FIG. 3 ) and can beused for mixing and/or suspending a culture or other solution withincontainer 18 (FIG. 2 ). Turning to FIG. 4 , drive motor assembly 18comprises a housing 304 having a top surface 306 and an opposing bottomsurface 308. An opening 310 extends through housing 304 from top surface306 to bottom surface 308. A tubular motor mount 312 is rotatablysecured within opening 310 of housing 304. Upstanding from motor mount312 is a locking pin 316. A drive motor 314 is mounted to housing 304and engages with motor mount 312 so as to facilitate select rotation ofmotor mount 312 relative to housing 304. Drive shaft 362 is configuredto pass through motor mount 312 so that engaging portion 372 of driveshaft 362 is retained within motor mount 312 and locking pin 316 ofmotor mount 312 is received within notch 376 of drive shaft 362. As aresult, rotation of motor mount 312 by drive motor 314 facilitatesrotation of drive shaft 362. Further discussion of drive motor assembly300 and how it engages with drive shaft 362 and alternative designs ofdrive motor assembly 300 are discussed in US Patent Publication No. US2011/0188928 A1, published Aug. 4, 2011 which is incorporated herein byspecific reference.

Continuing with FIG. 1 , arm assembly 302A is used to adjust theposition of drive motor assembly 300 and thereby adjust the position ofdrive shaft 362 (FIG. 5 ) and impeller 64 (FIG. 2 ) mounted on the endthereof. As mentioned above and as will be discussed below in greaterdetail, the ability to adjust the position of impeller 64 enablesoptimal mixing of fluid within container 18. As depicted in FIG. 1 , armassembly 302A comprises a first housing 318A that is rigidly secured toupper end 84 of support housing 78. As shown in FIGS. 5 and 6 , slidablycoupled with first housing 318A is an elongated first support 320A. Ahandle 410 is mounted to first support 320A for use in manually raisingand lowering first support 320A. First housing 318A and first support320A are orientated such that first support 320A can slide vertically upand down along a first axis 322A. In an alternative embodiment, firsthousing 318A and first support 320A can be disposed so that axis 322A isdisposed at an angle in a range between 0° to about 30° relative tovertical. Other angles can also be used.

In one embodiment of the present invention, means are provided forselectively locking first support 320A to first housing 318A atdifferent locations along axis 322A. In one embodiment of the presentinvention as shown in FIG. 6 , such means comprises holes 324A formed atspaced apart locations along first housing 318A and a spring activatedpin 326A mounted to first support 320A. By pulling out pin 326A, firstsupport 320A is free to slide vertically up and down along axis 322A. Byreleasing or pushing in pin 326A, pin 326A is received within acorresponding hole 324A so as to lock first support 320A in place. It isappreciated that any number of conventional clamps, pins, screws,latches, fasteners, or the like can be used for securing first support320A to first housing 318A. Indicia or markings can be formed along thesurface of first support 320A and/or first housing 318A to indicate therelative position of first support 320A.

Returning to FIG. 5 , in one embodiment a lift assist 412 is providedfor assisting in raising and lowering first support 320A and drive motorassembly 300. In the depicted embodiment, lift assist 412 comprises acylinder 414 having a first end pivotably coupled with the upper end offirst support 320A and an opposing second end pivotably coupled with thelower end of first housing 318A or with support housing 78. Cylinder 412is resiliently compressible. For example, cylinder 412 can comprise twonested cylinders halves having a spring or compressible gas disposedtherebetween. Cylinder 412 is positioned so that when first support 320Ais lowered, cylinder 412 is resiliently compresses so that the producedresilient force can subsequently be used to assist the operator inraising first support 320A and drive motor assembly 300. Lift assist 412thus permits an operator to easily and smoothly raise and lower firstsupport 320A with drive motor assembly 300 mounted thereon. In otherembodiments, it is appreciated that lift assist 412 can be automated toraise and lower first support 320A by activating a switch or through theuse of a controller. In those embodiments, lift assist 412 can beoperated through the use of an electrical motor or through use ofpneumatic or hydraulic systems.

First support 320A terminates at an upper end 330A. Mounted on upper end330A is a frame 416 having a side face 418. A second support 346A isrotatably mounted to side face 418 of frame 416. Second support 346A ismounted so that it rotates about a second axis 348A relative to frame416. Second axis 348A can be disposed in a horizontal plane or at anangle in a range between about 0° to about 30° relative to thehorizontal. Axis 348A can thus be perpendicular to axis 322A. Drivemotor assembly 300 is secured to second support 346A such that rotationof second support 346A facilitates concurrent rotation of drive motorassembly 300.

One embodiment of the present invention also includes means for lockingsecond support 346A at different angles about second axis 348A. By wayof example and not by limitation, a spring activated pin 350A is mountedon an arm of second support 346A. When pin 350A is retracted, secondsupport 346A is free to rotate about second axis 348A. As pin 350A isreleased or advanced inward, pin 350A is received within one of aplurality of holes formed on side face 418 of frame 416. As a result,second support 346A is thereby precluded from further rotation. Otherconventional fastening techniques can also be used. In otherembodiments, it is appreciated that second support 346A can be automatedto rotate by activating a switch or through the use of a controller suchas discussed above with regard to lift assist 412.

In view of the foregoing, first support 320A can facilitate verticalmovement of drive motor assembly 300 while second support 346A canfacilitate tilting of drive motor assembly 300. Because drive shaft 362and impeller 64 move concurrently and proportionally with drive motorassembly 300, adjustable arm assembly 302A can thus be used toselectively position the vertical height and tilt of impeller 64.

During use, arm assembly 302A is used to properly position drive motorassembly 300 so that rotational assembly 48 (FIG. 2 ) can be coupledwith drive motor assembly 300. Specifically, as depicted in FIG. 7 ,housing 304 of drive motor assembly 300 has an open access 384 that isrecessed on a front face 386 so as to communicate with opening 310extending through housing 304. Access 384 is in part bounded by asubstantially C-shaped first side wall 388 that extends up from bottomsurface 308, a concentrically disposed substantially C-shaped secondside wall 390 disposed above first side wall 388 and having a diameterlarger than first side wall 388, and a substantially C-shaped shoulder392 extending between side walls 388 and 390. As shown in FIG. 2 , adoor 394 is hingedly mounted to housing 304 and selectively closes theopening to access 384 from front face 386. Returning to FIG. 7 , door394 is secured in a closed position by a latch 396. Positioned on firstside wall 388 is a section 398 of a resilient and/or elastomericmaterial such as silicone. Other sections 398 of similar materials canalso be positioned on first side wall 388 or the interior surface ofdoor 394.

As depicted in FIG. 8 , to facilitate attachment of rotational assembly48 to housing 304, with door 394 rotated to an open position, rotationalassembly 48 is horizontally slid into access 384 from front face 386 ofhousing 304 so that a support flange 400 radially outwardly extendingfrom an upper end of rotational assembly 48 rests on shoulder 392 ofaccess 384. Rotational assembly 48 is advanced into access 384 so thatthe passage extending through hub 54 of rotational assembly 48 alignswith the passage extending through motor mount 312 (FIG. 4 ). In thisposition, door 394 is moved to the closed position and secured in theclosed position by latch 396. As door 394 is closed, casing 50 ofrotational assembly 48 is biased against the one or more sections 398(FIG. 7 ) of resilient material so as to clamp rotational assembly 48within access 384 and thereby prevent unwanted rotational movement ofcasing 50 relative to housing 304 of drive motor assembly 300.

Once rotational assembly 48 is secured to drive motor assembly 300,drive shaft 362 (FIG. 2 ) can be advanced down through drive motorassembly 300 and into impeller assembly 40 so as to engage impeller 64.Once drive shaft 362 is properly positioned, drive motor assembly 300 isactivated causing drive shaft 362 to rotate impeller 64 and thereby mixor suspend the fluid within container 18. When the processing iscomplete, drive shaft 362 is removed and rotational assembly 48 isseparated from drive motor assembly 300.

One advantage of being able to selectively adjust the vertical heightand tilt of impeller 64 through the use of arm assembly 302A is thatmixing assembly 10A can be used to maintain optimal mixing conditions offluid within a single container assembly 16 over a relatively largechange in fluid volumes. Specifically, the preferred position forimpeller 64 within container 18 to achieve optimal mixing can bedetermined using conventional techniques. This position can be measuredas a height from the bottom of container assembly 16 and is subject tothe height of the fluid within container assembly 16. Thus, as the fluidlevel increases within container assembly 16, the height of the locationfor impeller 64 to achieve optimal mixing also increases andvice-a-versa. Maintaining impeller 64 at the optimal location of mixinghelps to ensure that the fluid is homogeneous. This can be especiallyhelpful where mixing system 10A is functioning as a bioreactor orfermentor. In that case, the media, additives, and cells ormicroorganism should be continually turned over and homogeneouslydispersed to ensure that all of the cells and microorganism are beingcontinuously and uniformly fed and oxygenated.

It is also common that the volume of fluid within container assembly 16will vary significantly. For example, when first starting a bioreactoror fermentor, the seed inoculum of cells or microorganisms can bedispersed into a rather small volume of media within container assembly18. As the cells/microorganisms grow and multiple, more media andadditives can be progressively added to container assembly 16. By usingthe inventive system, the seed inoculum can be delivered into arelatively large container assembly 16 although only a small volume ofmedia is initially being used. In this initial step, impeller 64 islowered to achieve optimal mixing of the initial volume. As more fluidis progressively added into container 18, impeller 64 is progressivelyraised to maintain optimal mixing for the defined fluid volume. When theculturing is complete or it is otherwise desired to remove the solutionor suspension from container assembly 16, impeller 64 can again beprogressively lowered as the fluid within container assembly 16 isprogressively lowered. During the mixing process, it is typicallypreferred to maintain a positive gas pressure within container assembly16, such as in a range from 0.05 psi to about 2 psi to keep containerassembly 16 away from the rotating impeller assembly 40 and to keepcontainer 18 against heated support housing 78 to maintain temperatureregulation. This can be more important during low volume processing.

The ability to progressively add and remove relatively large amounts offluid from a single container while maintaining optimal mixing of thefluid eliminates or at least decreases the need to transfer the solutionto different sized containers for processing. By using a singlecontainer for processing as opposed to moving the fluid betweendifferent sized containers, the inventive system decreases processingdown time, avoids the expense of unnecessary containers, minimizes therisk of contamination, and minimizes potential damage tocells/microorganisms. The inventive system can operate over a relativelyhigh turn-down ratio. A “turn-down ratio” is the ratio of maximum tominimum volumes of fluid that a single container can process whilemaintaining acceptable mixing conditions. For example, a turn-down ratioof 10:1 means that if the initial volume that a mixing system canprocess at acceptable mixing conditions is 10 liters, the volume offluid with the container can be increased by a factor of 10, i.e., up to100 liters, and the system would still be able to process the fluid atacceptable mixing conditions. By using inventive mixing system 10A as abioreactor, fermentor, or other system that requires mixing orsuspension it is appreciated that containers assembly 16 can be sized tooperate with a turn-down ratio of at least 5:1, 10:1, 15:1, 20:1 orranges therebetween.

What constitutes acceptable mixing conditions is in part dependent uponwhat is being processed. When the system is functioning as a bioreactoror fermentor growing cells or microorganisms, the mixing should, ingeneral, assist in dispersal of the cells/microorganisms and sparged gasthroughout the solution so that the cells/microorganisms has access tothe required nutrients in the media and proper mass transfer is achievedwith the sparged gas. However, the mixing should not be so sever as toapply unwanted shear forces to the cells/microorganisms, createundesired splashing, or cause cavitation or a vortex in the solution,all of which can hamper the growth of cells/microorganisms.

In alternative embodiments, it is appreciated that adjustable armassembly 302A can have a variety of different configurations. Forexample, adjustable arm assembly 302A can be modified to permit selectlateral displacement of drive shaft 362 and impeller 64 that isindependent of tilting or vertical displacement. In addition, theadjustable arm assembly can be mounted on a separate docking stationthat removably couples with support housing 78. One specific example ofsuch an adjustable arm assembly is disclosed in US Patent PublicationNo. US 2011/0310696 A1, published Dec. 22, 2011 which is incorporatedherein by specific reference. One benefit of this design is that asingle adjustable arm assembly can be used with multiple differentsupport housings and particularly with support housings have differentheight and diameter sizes. For container assemblies 16 having differentsized diameters, impeller 64 may need to be adjusted laterally so thatimpeller 64 is centrally positioned to achieve optimal mixing. In othersituations, lateral displacement may be desirable to permit mixingcloser to or father away from the wall of container 18.

Depicted in FIG. 9 is another alternative embodiment of the presentinvention wherein like elements are identified by like referencecharacters. In this embodiment drive motor assembly 300 operates with acontainer 404 that is an open top liner. Container 404 is positionedwithin chamber 92 of support housing 78 so that is drapes over annularlip 94 (FIG. 1 ). This configuration can be used as a lower costalternative for mixing non-sterile fluids. In this embodiment,rotational assembly 48 merely functions to secure impeller assembly 40to drive motor assembly 300 so that it does not unintentionally slideoff of drive shaft 362. In alternative embodiments, because rotationalassembly 48 is no longer forming a sealed fluid connection with thecontainer, rotational assembly 48 can be substantially simplified. Forexample, as shown in FIG. 10 , rotational assembly 48 can be replaced bya clamp 406 that secures tubular connector 44 to drive shaft 362.Further alternative embodiments with regard to impeller assembly 40 andhow they can be attached to drive motor assembly 300 or drive shaft 362are discussed in US Patent Publication No. US 2011/0188928 A1, publishedAug. 4, 2011 which is incorporated herein by specific reference.

Depicted in FIG. 11 is another alternative embodiment of an inventivemixing system 10B incorporating features of the present invention. Likeelements between systems 10A and 10B are identified by like referencecharacters. In general, mixing system 10B comprises support housing 78,cart 80A on which on which support housing 78 rests, drive motorassembly 300, an adjustable arm assembly 302B which supports drive motorassembly 300, container assembly 16 that is supported within supporthousing 78, and drive shaft 362 (FIG. 12 ) that extends between drivemotor assembly 300 and impeller assembly 40 of container assembly 16.The primary difference between mixing systems 10A and 10B is themodification of adjustable arm assembly 302B relative to adjustable armassembly 302A.

As depicted in FIGS. 12 and 13 , adjustable arm assembly 302B is in theform of a programmable robotic arm having multiple axes of rotation thatenable the robotic arm to periodically or continuously adjust theposition of impeller 64 three dimensionally, including tilting ofimpeller 64. Specifically, adjustable arm assembly 302B includes a lowerbase 430 that is mounted on a support platform 432 projecting fromsupporting housing 78. An upper base 434 is mounted on lower base 430 bya first swivel joint 436. First swivel joint 436 permits upper base 434to rotate relative to lower base 432 about a first axis 438 that isvertically oriented or can be offset from vertical over an angel in arange from about 0° to about 30°. A first motor 440A is mounted on upperbase 434 and engages with first swivel joint 436 for controllingrotation of upper base 434 about first axis 438.

Mounted to upper base 434 is a first arm 442 having a first end 444 andan opposing second end 446. First end 444 is rotatably mounted to upperbase 434 by a second swivel joint 448. Second swivel joint 448 rotatesabout a second axis 450 that is horizontally disposed and/or extendsperpendicular to first axis 438. A second motor 440B engages with secondswivel joint 448 for controlling rotation of first end 444 of first arm442 about second axis 450.

Arm assembly 302B also includes a second arm 452 having a first end 454and an opposing second end 456. First end 454 of second arm 452 isrotatably mounted to second end 446 of first arm 442 by way of a thirdswivel joint 458. Third swivel joint 458 rotates about a third axis 460that is also horizontally disposed and/or is parallel to second axis450. A motor 440C engages third swivel joint 458 for controllingrotation of first end 454 of second arm 452 about third axis 460.

Drive motor assembly 300 is rotatably coupled to second end 456 ofsecond arm 452. Specifically, a flange 462 projects out from a side ofhousing 304 of drive motor assembly 300. Secured to flange 462 is amount 464. Second end 456 of second arm 452 is rotatably mounted tomount 464 by a fourth swivel joint 466. Fourth swivel joint 466 rotatesabout a fourth axis 468 which is also horizontally disposed and/or isparallel to axis 450 and 460. A motor 440D is shown mounted at first end454 of second arm 452 and is operably coupled with fourth swivel joint466 for controlling rotation of drive motor assembly 300 about fourthaxis 468. In alternative embodiments, it is appreciated that motor 440can be secured to mount 464.

In one embodiment, a fifth swivel joint 470 can be formed on second arm452 at a location between opposing ends 454 and 456. Swivel joint 470rotates about a fifth axis 472 that centrally extends along the lengthof second arm 452 and extends orthogonal to axis 460 and 468. Motor 440Eis disposed at first end 454 of second arm 452 and is operably coupledwith fifth swivel joint 470 so as to enable drive motor assembly 300 torotate about fifth axis 472. In the embodiment depicted, second arm 452can also be a telescoping arm that can selectively lengthen and retract.A motor 440F couples with second arm 452 to control the telescopingexpansion and contraction of second arm 452.

As will be discussed below in greater detail, in view of the multipleswivel joints and the selective telescoping of second arm 452,adjustable arm assembly 302B can be manipulated to position impeller 64over a wide range of positions and orientations within containerassembly 16 to facilitate optimum mixing therein. Furthermore,adjustable arm assembly 302B can be programmed to periodically orcontinuously adjust the position of impeller 64 to optimize mixingwithin container assembly 16. For example, each of motors 440A-440F ofadjustably arm assembly 302B and drive motor 314 of drive motor assembly300 can be electrically connected to electrical coupler 474. In turn,electrical coupler 474 can be selectively coupled to a controller 475having a central processing unit that can be programmed tosimultaneously control operation of all the motors and thereby controlnot only the speed of rotation of impeller 64 but also its desiredposition. For example, as will be discussed below, adjustable armassembly 302B can be used to move impeller 64 along a continuous2-dimensional path or 3-dimensional path.

In one embodiment, each of motors 440A-F comprises an electrical motorwhich communicates with the corresponding swivel joints through a directdrive, gear drive, pulley system, or the like. In alternativeembodiments, one or more motors can drive the swivel joints throughpneumatics, hydraulics or other conventional systems. Thus, the motorsneed not be mounted directly to arm assembly 302B but can be locatedremotely with fluid lines coupled to the assembly for controllingmovement.

Due to the adjustability and automated controlled movement of impeller64 resulting from adjustable arm assembly 302B and the differentconfigurations for container 18, mixing system 10B can operate over ahigher turn-down ratio than prior embodiments. For example, mixingsystem 10B can be used to produce turn-down ratios in the range of atleast east 50:1 or 80:1 and more commonly at least 20:1, 30:1, or 40:1.Other ratios can also be achieved.

During use of mixing systems 10A and 10B rotational assembly 48 (FIG. 2) of container assembly 16 is directly coupled within drive motorassembly 300. The flexible nature of container 18 enables adjustable armassemblies 302A and 302B to freely tilt and to move vertically andhorizontally each of drive motor assembly 300, rotational assembly 48,drive shaft 362 and impeller 64 during the rotation of impeller 64.However, in some situations container 18 may need to be oversizedrelative to support housing 78 when used with adjustable arm assemblies302A and 302B so that when container 18 is filled to its maximum levelwith fluid, there is still a sufficient amount of flexible container 18extending above the fluid level to permit free movement of the assembleddrive motor assembly 300, rotational assembly 48, drive shaft 362 andimpeller 64.

Controller 475 can be electronically coupled with a variety ofcomponents of both mixing systems 10A and 10B that control operationalparameters. For example, as depicted in FIG. 14 , controller 475 can beelectrically coupled with drive motor assembly 300, arm assembly 302B,gas regulator 500, fluid temperature regulator 502, fluid sensors 504and volume sensors 506. Gas regulator 500 controls that flow rate andmixture of gasses that are delivered to sparger 34 through gas line 36(FIG. 2 ). As previously discussed, the gases typically include air thatis selectively combined with oxygen, carbon dioxide and/or nitrogen butother gases can also be used. Fluid temperature regulator 502 controlsoperation of the boiler that is used to heat and pump the fluid throughjacketed support housing 78 for regulating the temperature of the fluidwithin container 18. Fluid sensors 504 are coupled with container 18 orotherwise interact with the fluid therein for detecting properties ofthe fluid. Examples of fluid sensors 504 include temperature probes, pHprobes, dissolved O₂ probes, dissolved CO₂ probes, optical densitysensors that sense the density of the fluid, conductivity sensors, andviscosity sensors.

Volume sensors 506 can come in a variety of different configurations andare used to detect the volume or level of fluid within container 18. Forexample, as depicted in FIG. 11 , in one embodiment volume sensors 506comprise load cells 476 positioned between support housing 78 and cart80A. Load cells 476 provide signals to controller 475 that reflect theweight or change in weight of support housing 78 due to the addition orsubtraction of fluid in container 18. In turn, controller 475 uses thisinformation in an algorithm to calculate the volume or level of fluidwithin container 18. In one embodiment of the present invention meansare provided for sensing the volume or level of fluid within container18. One example of such means includes load cells 476 as discussedabove. In alternative embodiments, load cells 476 can be replaced withoptical sensors or pressure sensors located along the side of supporthousing 78 or container 18 and which sense the height of the fluid. Inother embodiments floats or other mechanical sensors can be used tomeasure the rising or lower of the fluid within container 18. Otherconventional techniques can also be used.

In one example of use, mixing systems 10A and 10B can be used as abioreactor or fermentor for growing cells or microorganisms. A firstsolution having a first volume is dispensed into compartment 28 ofcontainer 18 and comprises media, cells or microorganisms, and othercomponents as desired. The solution can be a small volume that containsan initial seed inoculum or a larger volume of a partially processedculture that is being moved to a larger container for further growth. Byusing a corresponding adjustable arm assembly 302A or B, impeller 64 ismoved to the desired location within compartment 28 to facilitatedesired mixing for the first volume of fluid. Impeller 64 is activatedand set to run at a defined speed causing mixing of the solution whilegas is delivered to sparger 34 to oxygenate and regulate other masstransfer with the solution. In addition, fluid temperature regulator 502is set to heat the fluid within container 18 to a desired level. Underthese conditions, the cells/microorganisms are left to propagate withinthe solution.

As the cell density increases, additional media can be added either at acontinuous flow rate or as a batch at staggered intervals. In eitherevent, the media is added so that the density of thecells/microorganisms does not exceed a predetermined maximum density foroptimal growth and does not drop below a predetermined minimum densityfor optimal growth. The density values are generally more important forthe growth of cells than microorganisms.

If the fluid volume increases within container 18 while impeller 64 isheld at a constant speed and position, the mixing efficiency of thefluid will eventually begin to decrease. A decrease in mixing efficiencycan decrease the growth rate of the cells/microorganisms and eventuallyresult in cells/microorganisms dying due to a lack of proper masstransfer and the inability to access and consume needed nutrients fromthe media. According, to maintain desired mixing without transferringthe solution to a new container, once the solution has reached apredetermined second volume or height within container 18, such asdetermined by volume sensor 506, impeller 64 is raised to a secondposition within container 18 which is more optimal for mixing thesolution at the increased volume. This adjustment of impeller 64 can bethrough manual manipulation of arm assembly 302B, manually inputtingcommands into controller 475 for repositioning arm assembly 302B, orpreprogrammed automatic adjustment of arm assembly 302B by controller475 based on inputs from volume sensor 506.

In situations where arm assembly 302 is being adjusted manually orthrough manual inputs, the interval between adjustments many be longerand the moved displacement of impeller 64 greater. The addition ofsolution and the vertical movement of impeller is at a slower rate forsmall volumes of fluid and increases as the size of the cultureincreases. However, in some situations where the vertical movement ofimpeller 64 is in a single movement, the displacement of impeller may beat least 5 cm, 10 cm, 20 cm, or more. In contrast, where impeller 64 isbeing automatically adjusted through programmed controller 475, themovement of impeller 64 can be at much shorter intervals and at muchsmaller increments and in some situations, such as for large volumes offluid, the movement of impeller 64 can be continuous.

It is envisioned that impeller 64 will be moved to the second elevatedposition during continuous operation of impeller 64. In some situations,however, impeller 64 can be stopped, moved to the second position, andthen restarted. Once impeller 64 is moved to the second position, theprocess is repeated. That is, the density of the cells/microorganisms ismonitored, additional media is added to the culture to regulate density,and impeller 64 is moved, either continuously or in one or more steps,to a third position to continue to maintain desired mixing conditions.In contrast to adding media based on cells/microorganism density, themedia can be added at a fixed rate, at set intervals, or based on othermeasured processing parameters. The process of adjusting impeller 64 iscontinued until container 18 is either filled to a desired level and thesolution is then moved to a larger container 18 for further processingor the desire batch volume is reached. Where a desired batch volume isreached, it is appreciated that impeller 64 can also be incrementally orcontinuously lowered within container 18 as solution is drawn out ofcontainer 18.

It is appreciated that as the volume of solution increases withincontainer 18 and/or impeller 64 is raised, that other operatingparameters also need to be continually monitored and adjusted. Forexample, the concentrations and rate of gas introduced through sparger34 will likely need to be modified so that the pH and dissolved CO₂ andO₂ are within desired limits. Likewise, the temperature or flow rate ofthe heated fluid passing through jacketed support housing 78 may need tobe adjusted to control the desired temperature of the increased volumeof fluid.

In addition to or instead of adjusting the vertical height of impeller64, the speed, tilt, and/or lateral position of impeller 64 can also beadjusted. For example, prior to or concurrent with the vertical raisingor lower of impeller 64, the rotational speed of impeller 64 can beadjusted to account for the increase or decrease in fluid volume. Thisadjustment can be manual or automatic through controller 475 based onthe sensed change in volume or fluid height. For example, when the fluidvolume within container 18 gets relatively small, the speed of impeller64 necessary to maintain proper mixing can be reduced. Failure to reduceimpeller speed in low fluid volumes can result in unwanted gasentrapment and splashing of the solution. Likewise, as the fluid volumeincreases, it may be necessary to increase the impeller speed inaddition to moving the impeller to achieve a desired mixing.

Tilting impeller 64 can adjust the circulation flow. For example,increasing lateral tilt decreases radial flow in favor of a more randomflow. Tilting impeller 64 by a few degrees may thus be sufficient tomaintain desired mixing at some increased fluid volumes. Periodic orcontinuous tilting of impeller 64 back and forth over a range of anglescan also be used as one mechanism for maintaining desired mixingconditions.

Lateral displacement of impeller 64 within container 18 also influencesthe flow pattern of the fluid within container 18 and thus the mixingthereof. Depending on the configuration of container 18 within supporthousing 78, optimal fluid mixing may be achieved by locating impeller 64at different lateral positions within container 18 as the level of thefluid within container 18 changes. In addition, periodic or continuouschanging of the lateral position of impeller 64 can periodically orcontinuously change the flow pattern of the fluid and thus be used toachieve desired mixing conditions. For example, controller 475 can beprogrammed to operate arm assembly 302B so that impeller 64 isperiodically or continuously moved along a fixed or random horizontal2-dimensional path within container 18. This may be particularly helpfulwhere the fluid volume in container 18 is so large that keeping impeller64 at a fixed location will not be sufficient to maintain desired mixingof the entire fluid volume.

In still other embodiments, it is appreciated that controller 475 can beprogrammed to operate arm assembly 302B so that rotational speed, tilt,lateral displacement and/or vertical displacement of impeller 64 can beperiodically or continuously adjusted to achieve desired mixingconditions as the volume of fluid increases. For example, in bioreactorsand fermentors it is desirable to continually maintain a high turnoverrate of the fluid within container 18 to ensure that the cells and/ormicroorganisms are uniformly dispersed and are exposed to a uniform feedmaterial. One approach to increasing turnover is to just increase theimpeller rotation speed. However, by just increasing impeller rotationspeed, a vortex can be formed in the fluid that can decrease fluidturnover. That is, all the fluid is simply spinning within container 18but without effectively mixing. The formation of a vortex can alsoentrap gas within the fluid which can be detrimental to the cells. Tocounter the formation of a vortex, controller 475 can be programmed tocontinuously or periodically adjust the position and/or orientation ofimpeller 64. For example, impeller 64 can be adjusted horizontally,vertically and/or tilted in different orientations. By changing theposition and/or orientation of impeller 64 the force on the fluid ischanged which disrupts or prevents the formation of a vortex andproduces a more turbulent flow. Thus, controller 475 can be programmedto operate arm assembly 302B so that impeller 64 is periodically orcontinuously moved along a fixed or random 3-dimensional path withincontainer 18. In addition to moving along the 3-dimensional path, thespeed and tilt of impeller 64 can also be adjusted.

In one embodiment to help prevent the formation of vortexes, drive shaft362 and associated impeller 64 can be moved in a pattern opposite to thedirection in which impeller 64 rotates. For example, FIG. 17 shows across sectional top plan schematic view of container assembly 18 havingdrive shaft 362 disposed therein. Drive shaft 362, and thus impeller 64,can be rotated by drive motor assembly 300 in a clockwise direction asidentified by arrow 478. Concurrently, however, adjustable arm assembly302B can be moving drive shaft 362 and impeller 64 within containerassembly 16 in a counterclockwise path along arrow 480. This movement inopposite directions can help eliminate the formation of a vortex.

This automatic adjusting of the impeller location and speed can have asignificant influence during critical applications. For example, in thefinal fill volume of bioreactors, aluminum or other solutes, adjuvantsand/or suspensions are commonly added to boost or stabilize the dosepotency. In this case the dense materials can settle out very easily andthe solution must remain well mixed until the final few liters aredrained. By automatically adjusting the impeller location as the fluidlevel lowers there is a decreased chance of any unwanted settling.

In some embodiments, such as when cells are being grown on microcarriers in a bioreactor, it can be desirable to minimize impeller speedsince contact between the cells and a fast rotating impeller can damagethe cells. As mentioned above, the speed of the impeller is oftendictated by the need for maintaining a continuous turnover of the fluid.To help minimize damage by impeller 64 while maintaining desired fluidmixing, adjustable arm assembly 302B can continuously or periodicallymove impeller 64 in a horizontal pattern within container 18, such asalong the circular path of arrow 480 in FIG. 16 . This horizontalmovement of impeller 64 enables impeller 64 to have lower tip speed orrotational speed which minimizes cell damage but still maintain agenerally uniform mixing of the fluid. It is appreciated that impeller64 can be moved in a variety of different patterns such as a triangle orother polygonal patterns or in a repeating wave pattern. Varying thetilt of impeller 64, either in conjunction with or independent of thehorizontal movement of impeller 64, can also help achieve uniform mixingat low impeller speed.

In other embodiments, it appreciated that controller 475 can be operatedby a automated program that uses computational fluid dynamic modeling inconjunction with sensed critical process variables to provide real timefeedback for dynamically controlling the position, speed, orientation,and/or movement pattern of impeller 64. For example, based on input fromfluid sensors 504 and volume sensors 506, controller 475 can monitor theprocess variables of volume, gassing rate, pH, dissolved O₂, dissolvedCO₂, conductivity, density, viscosity, and/or flow pattern of thesolution. When any of the process variables fall outside of a predefinedrange, controller 475 automatically makes adjustments to gas regulator500, fluid temperature regulator 502, arm assembly 302B and/or drivemotor assembly 300 to correct the process variable. The algorithm usedto correct the process variable is based on known computational fluiddynamic modeling techniques and empirical data. Where applicable,controller 475 can dynamically regulate the position, speed,orientation, and/or movement pattern of impeller 64 through arm assembly302B and drive motor assembly 300 to correct the processing variable.For example, if the cell or microorganism density is found to be toohigh at a certain location within container 18, as could be determinedby multiple optical density sensors couple about container 18, impeller64 may be automatically moved to a defined location within container 18to improve the overall mixing of the fluid or may be temporarily movedcloser to the location where the cells/microorganism have the highestdensity so that those cells/microorganism are properly mixed.Alternatively, as controller 475 senses that the volume of fluid withincontainer has reached a predefined level, controller 475 canautomatically set impeller 64 to move to certain locations or to travelalong a certain 2- or 3-dimensional path. It is appreciated that thepossible alternatives as to when and how the position, speed,orientation, and/or movement pattern of impeller 64 can be adjusted areextensive. The programmed system, however, continuous to make dynamicadjustments to the system based on real time sensed processingparameters until processing of the fluid is completed.

To enable mixing of solutions at very low volumes, it is appreciatedthat floor 88 or the lower end of support housing 78 can be made havinga steep conical configuration into which container 18 having acomplementary configuration can be received and impeller 64 can belowered. For example, depicted in FIG. 15 is a cross sectional side viewof one embodiment of support housing 78 in which floor 88 has a conicalconfiguration with an interior surface 482 sloping at an angle αrelative to the horizontal. The angle α can be in a range between about35° to about 70° with about 45° to about 70° and about 55° to about 70°being more common. Other angles can also be used. By inwardly taperingthe floor or lower end of support housing 78, smaller volumes ofsolution can be formed within container 18 that retain a sufficientdepth and width to enable impeller 64 to be lowered therein. Impeller 64can thus be submerged and rotated within the smaller volumes to maintainproper mixing.

Depicted in FIG. 16 is another alternative embodiment of how a containerand corresponding support housing can be formed to permit proper mixingat both large and small volumes of solution. As shown therein, a supporthousing 78A is formed having a sidewall that extends down to floor 88.Centrally formed on floor 88 is a receiver 482 that bounds a recess 484.In the depicted embodiment, receiver 482 and recess 484 have asemi-spherical configuration. In other embodiments, receiver 482 andrecess 484 can have other shapes. Floor 88 is annular and slopes towardreceiver 482. A port 486 is centrally formed through the bottom ofreceiver 482.

Container 18 is shown having floor 424. Centrally secured to floor 424,such as by welding, is a dish 488 which bounds a cavity 490. Fluid line426 couples with the bottom of dish 488 so as to communicate with cavity490. During assembly, dish 488 is received and supported within receiver482 so that fluid line 426 passes out through port 486. Receiver 482typically has a configuration complementary to dish 488. Dish 488 can becomprised of a rigid or semi-rigid material such as a plastic orcomposite. Alternatively, dish 488 can be formed from a polymeric sheetor film, such as that used to form container 18.

As the solution is drained out of container 18 or as the solution isinitially dispensed into container 18, the solution gathers within dish488. Again, dish 488 has a width and depth that enables impeller 64 tobe lowered therein. Impeller 64 can thus be submerged and rotated withincavity 490 to maintain proper mixing of the relatively small volume offluid container therein. Dish 488 is typically configured so that cavity490 has a semi-spherical configuration or an elongated semi-sphericalconfiguration. However, cavity 490 can also be formed into otherconfigurations that will receive impeller 64. Cavity 490 can have avolume in a range between about 5 liters to about 40 liters with about 5liters to about 20 liters or 5 liter to about 10 liters being morecommon.

As with other embodiments, it is appreciated that adjustable armassembly 302B can be used in association with container 404, depicted inFIG. 9 , which is an open top liner. Again, rotational assembly 48 canbe used to secure impeller assembly 40 to drive motor assembly 300 or,as shown in FIG. 10 , rotational assembly 48 can be replaced by a clamp406 that secures tubular connector 44 to drive shaft 362.

In another alternative embodiment, it is appreciated that impellerassembly 40 (FIG. 3 ) can be eliminated. For example, as shown in FIG.18 , container 18 has a drive shaft 362A that projects directly intocompartment 28. Drive shaft 362A can have substantially the sameconfiguration as drive shaft 362 except that an impeller 64A is rigidlyfixed directly to the end thereof within compartment 28. A dynamic seal492 is used to form an aseptic seal between container 18 and shaftsection 366 of drive shaft 362A. Seal 492 also enables drive shaft 362Ato rotate relative to container 18 while maintaining the aseptic seal.

Drive shaft 362A includes head section 364 which threads or otherwisesecures to shaft section 366 as shown in FIG. 3 . Head section 364 canthus be attached to drive motor assembly 300 (FIG. 11 ) prior tosecuring head section 364 to shaft section 366. Alternatively, driveshaft 362A can be formed as a single integral member and a differentstructure can be used to secure drive shaft 362A to drive motor assembly300. Shaft section 366 or the entire drive shaft 362A can be made from aplastic or composite material that is disposed of after use.Alternatively, shaft section 366 or the entire drive shaft 362A can bemade of a metal that is sterilized and reused.

Adjustable arm assembly 302B is only one example of a programmablerobotic arm that can be used with the present invention. It isappreciated any number of conventional robotic arms can be used in thepresent invention. Furthermore, it is appreciated that other roboticarms need not have all of the degrees of freedom incorporated intoadjustable arm assembly 302B. For example, the robotic arm may only beable to move impeller 64 vertically up and down but not move laterallyor tilt. Other robotic arms may have any combination of being able tomove impeller 64 vertically, laterally, and/or tilt. Thus, the roboticarms can be designed to move impeller 64 in one dimension, twodimensions, or three dimensions. It is likewise appreciate thatadjustable arm assembly 302B need not be in the shape of a conventionalrobotic arm. For example, adjustable arm assemblies 302A can be modifiedto incorporate motors for moving the various supports and those motorscan be electronically coupled to controller 475 for automaticallycontrolling the movement of impeller 64.

The above discussed embodiments disclose impeller 64 as the sole mixingelement. In other embodiments, however, it is appreciated that impeller64 can be replaced with other mixing elements. For example, amagnetically driven impeller could be rotatably mounted on the end ofdive shaft 362. Although drive shaft 362 could still be used to elevate,tilt, or move the impeller in a pattern, a magnetic drive source locatedoutside of container 19 could be used to rotate the impeller. As such,drive motor assembly 300 could be eliminated. In another embodiment, theends of a fluid inlet tube and a fluid outlet tube could be mounted onthe end of draft shaft 362. Fluid could be drawn out of container 18through the outlet tube while the fluid is pumped back into container 18through the inlet tube. The fluid being drawn out of and pumped intocontainer 18 can mix the remaining fluid within container 18. Again,drive shaft 362 can be used to elevate, tilt, or move the ends of thetubes. In another embodiment, the end of a gas line can be mounted tothe end of drive shaft 362. The gas blown out of the gas line can beused to mix the fluid. In still other embodiments, impeller 64 can bereplaced with a paddle, baffle, or other structure that can be swiveled,rotated, reciprocated, pivoted or otherwise moved within container 18for mixing the fluid therein.

The inventive fluid mixing systems achieve a number of benefits. By wayof example, the inventive systems permit fluids, and particularly celland microorganism cultures, to be processed within a single containerover a significantly larger turn down ratio than prior systems. Notably,the fluid mixing systems enable fluids to be mixed within a singlecontainer at a desired turnover or mixing rate over a broad range offluid volumes. As a result of eliminating or reducing the number ofdifferent containers that the fluid has to be transferred into duringprocessing, there is less downtime where the fluid is not being mixed orotherwise treated, less material waste, lower labor costs, and less riskof fluid contamination. Furthermore, the inventive mixing systemsprovide improved mixing capabilities and improved fluid processingcapabilities.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

1.-28. (canceled)
 29. A fluid mixing system comprising: a supporthousing having an interior surface bounding a chamber; an impellerdisposed within the chamber; a drive shaft coupled with the impellersuch that rotation of the drive shaft facilitates rotation of theimpeller; a drive motor assembly coupled with the drive shaft and beingadapted to rotate the drive shaft; an adjustable arm assembly mounted onthe support housing and coupled with the drive motor assembly forproviding three-dimensional movement to the impeller, the arm assemblycomprising: a lower base coupled to the support housing, an upper basemounted on the lower base by a first swivel joint for rotation around afirst axis, and a first arm having a first end and an opposing secondend, the first end of the first arm coupled to the upper base by asecond swivel joint for rotation around a second axis, the second axisbeing orthogonal to the first axis.
 30. The fluid mixing system asrecited in claim 29, further comprising a second arm having a first endand an opposing second end, the first end of the second arm rotatablymounted to the second end of the first arm by a third swivel joint forrotation around a third axis, the third axis being parallel to thesecond axis.
 31. The fluid mixing system as recited in claim 30, furthercomprising a fourth swivel joint interposed between the second end ofthe second arm and the drive motor assembly for rotation around a fourthaxis, the fourth axis being parallel to the second axis.
 32. The fluidmixing system as recited in claim 31, further comprising a fifth swiveljoint coupled to the second arm for rotation of the drive motor assemblyaround a fifth axis, the fifth axis being orthogonal to the second,third, and fourth axes.
 33. The fluid mixing system as recited in claim32, further comprising one or more motors to drive the first, second,third, fourth, and fifth swivel joints through a pneumatic or hydraulicmechanism.
 34. The fluid mixing system as recited in claim 30, whereinthe second arm is a telescopic arm configured to lengthen or contractselectively.
 35. The fluid mixing system as recited in claim 29, whereina movement of the adjustable arm assembly is controlled by an electricalcontroller.
 36. The fluid mixing system as recited in claim 35, furthercomprising means for sensing a fluid volume or change in fluid volumewithin the chamber, the electrical controller being in electricalcommunication with the means for sensing.
 37. The fluid mixing system asrecited in claim 35, wherein the electrical controller is programmable.38. The fluid mixing system as recited in claim 35, wherein theelectrical controller is programmed to automatically adjust a position,tilt, or movement pattern of the impeller based on one or more fluidproperties of a fluid within the chamber.
 39. The fluid mixing system asrecited in claim 29, further comprising a flexible bag at leastpartially disposed within the chamber of the support housing, arotational assembly mounted to the flexible bag, the rotational assemblycomprising: a casing secured to the flexible bag; a hub rotatablymounted to the casing, the hub having a passageway extendingtherethrough, the drive shaft extending through the passageway of thehub; and an elongated tubular connector extending between the hub andthe impeller, the drive shaft being disposed within the tubularconnector.
 40. The fluid mixing system as recited in claim 39, furthercomprising a compartment bounded by an interior surface of the flexiblebag, the interior compartment of the flexible bag being closed andsterile.
 41. The fluid mixing system as recited in claim 39, wherein theflexible bag comprises an open top liner.
 42. The fluid mixing system asrecited in claim 39, further comprising a dynamic seal formed directlybetween the drive shaft and the flexible bag.
 43. The fluid mixingsystem as recited in claim 40, further comprising a fluid disposedwithin the compartment of the flexible bag, the fluid comprising mediaand cells or microorganisms.